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The Role of Necroptosis in Cerebral Ischemic Stroke

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Abstract

Cerebral ischemia, also known as ischemic stroke, accounts for nearly 85% of all strokes and is the leading cause of disability worldwide. Due to disrupted blood supply to the brain, cerebral ischemic injury is trigged by a series of complex pathophysiological events including excitotoxicity, oxidative stress, inflammation, and cell death. Currently, there are few treatments for cerebral ischemia owing to an incomplete understanding of the molecular and cellular mechanisms. Accumulated evidence indicates that various types of programmed cell death contribute to cerebral ischemic injury, including apoptosis, ferroptosis, pyroptosis and necroptosis. Among these, necroptosis is morphologically similar to necrosis and is mediated by receptor-interacting serine/threonine protein kinase-1 and -3 and mixed lineage kinase domain-like protein. Necroptosis inhibitors have been shown to exert inhibitory effects on cerebral ischemic injury and neuroinflammation. In this review, we will discuss the current research progress regarding necroptosis in cerebral ischemia as well as the application of necroptosis inhibitors for potential therapeutic intervention in ischemic stroke.

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Abbreviations

LAAS:

Large artery atherosclerosis

tPA:

Tissue plasminogen activator

PCD:

Programmed cell death

RIPK1:

Receptor-interacting protein kinase 1

RIPK3:

Receptor-interacting protein kinase 3

MLKL:

Mixed lineage kinase domain-like protein

TNF:

Tumor necrosis factor

TLRs:

Toll-like receptors

IFNAR:

Interferon receptors

IFNAR:

Interferon receptors

ZBP1:

Z-DNA binding protein 1

TRADD:

TNF receptor-associated death domain,

cIAP1/2:

cellular inhibitor of apoptosis

TRAF2/5:

TNF receptor-associated factor 2/5

TAK1:

TGF-activated kinase 1

IKK:

IκB kinase

SMAC:

Second mitochondria-derived activator of caspase

CYLD:

Cylindromatosis

FADD:

Fas-associated death domain protein

RHIM:

RIP homotypic interaction motif

TRIF/ TICAM1:

TIR-domain-containing adapter-inducing interferon-β

ZBP1/DLM-1/DAI:

Z-DNA-binding protein 1

TLR3:

Toll-like receptor 3

Nec-1:

Necrostatin-1

MCAO:

Middle cerebral artery occlusion

OGD:

Oxygen-glucose deprivation

I/R:

ischemia/reperfusion

TAK1:

Transforming growth factor-activated kinase 1

MIP:

Myd88 inhibitory peptide

BBB:

Blood brain-barrier

EC:

Endothelium

ASIC1a:

Acid-sensing ion channel 1a

NSF:

N-ethylmaleimide-sensitive fusion ATPase

FHA:

Forkhead-associated

NDRG2:

N-myc downstream-regulated gene 2

pMCAO:

permanent middle cerebral artery occlusion

JNK:

The c-Jun N-terminal kinase

MAPKs:

Member of mitogen-activated protein kinases

AIF:

Apoptosis-inducing factor

DAMPs:

Damage-associated molecular patterns

HMGB1:

High mobility group box 1

BCP:

β-caryophyllene

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

MPTP:

Mitochondrial permeability transition pore

CHIP:

Carboxyl terminus of Hsp70-interacting protein

HSP90:

Heat shock protein 90

GA:

Geldanamycin

IL-1R1:

Interleukin-1 receptor 1

TRAF2:

Tumor necrosis factor receptor associated factor 2

Z-VAD:

Z-VAD-FMK

MALT1:

Mucosa-associated lymphoid tissue lymphoma translocator protein 1

tAIF:

truncated AIF

PCD:

Programmed cell death

Sirts:

Sirtuins

NAD+:

Nicotinamide adenine dinucleotide

ERK:

Extracellular signal-regulated kinase

ROS:

Reactive oxygens species

PGRN:

Progranulin

NLRP3:

NOD-like receptor family pyrin domain-containing 3

Nrf2:

Nuclear factor E2-related factor-2

IDO:

Indoleamine 2,3-dioxygenase

WMI:

White matter injury

PNS:

Panax notoginseng saponins

Ab4B19:

TrkB agonistic antibody

BDNF:

Brain-derived neurotrophic factor

PPO:

Pomelo peel oil

MD2:

Myeloid differentiation protein 2

Tat-CIRP:

Trans-trans-activating (Tat)-cold-inducible RNA binding protein

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Acknowledgements

We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

Funding

This work was supported by grants from Key Research and Development Program of Ningxia (No.2022BFH02012); National Natural Science Foundation of China (No.32170748); Shanghai Committee of Science and Technology (No. 21490714300); and Fundamental Research Funds for the Central Universities.

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  1. Qingsong Wang and Fan Yang contributed equally to this work.

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  1. College of Pharmacy, Ningxia Medical University, Hui Autonomous Region, Yinchuan, 750004, Ningxia, China

    Qingsong Wang, Fan Yang, Kun Duo, Yue Liu, Jianqiang Yu & Zhenyu Cai

  2. Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China

    Qihui Wu

  3. Shanghai Tenth People’s Hospital, School of MedicineTongji University Cancer Center, Tongji University, Shanghai, 200092, China

    Zhenyu Cai

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Zhen C. had the idea for the review article; Qing W., Fan Y., Kun D., Yue L., Jian Y. and Qi W. performed the literature search; Qing W., Fan Y. and Kun D. drafted the manuscript; Zhen C. critically revised the manuscript.

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Wang, Q., Yang, F., Duo, K. et al. The Role of Necroptosis in Cerebral Ischemic Stroke. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03728-7

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